1. Field of the Invention
The present invention relates to a composition comprising TIP41 expression or activity inhibitor, for increasing TRAIL sensitivity.
2. Description of the Related Art
Cancer is the biggest threatening disease to human society; it is generated due to a cell line mutation, which leads to uncontrollable and infinite divisions and immortality of the cells. Causes of cancers include external or environmental factors, such as chemicals, viruses, bacteria and ionizing radiation, and internal factors, such as congenital gene mutation (Klaunig & Kamendulis, Annu Rev Pharmacol Toxicol., 44:239-267, 2004).
Cancers found in early stages may be cured with surgeries, radiotherapies and chemotherapies; yet, their side-effects are being issued significantly as well, and patients of late-stage cancers and metastasis cancers end up with terminal illness, which cannot be treated with any specific cure. Also, there have been various biochemical mechanisms related to cancers and the cures have been developed as the follow-ups, yet fundamental cure for cancer has not been provided.
TRAIL (TNF Related Apoptosis Inducing Ligand) is a cytokine involved in TNF (Tumor Necrosis Factor) family, and this acts as a ligand inducing apoptosis by activating death receptor pathway. TRAIL has 4 receptors. Among these, DR 4/5 (Death Receptor 4/5) is known to be over-expressed in cancer cell line, while DcR 1/2 (Decoy Receptor 1/2) is reported in normal cell line. Unlike other receptors, decoy receptors do not have the death domain at the end of c-terminal, therefore, the death signal is not transmitted inside of cell. Thus, cancer treatment using TRAIL is considered as a next-generation anticancer agent having no side effects on normal cell.
Many anticancer agents and cancer repressors developed so far have been reported to have side effects, such as critical cytotoxicity on normal cell due to their nonspecific nature, and the resistance acquisition of cancer cell line due to high mutation rate. However, since it was reported that TRAIL induces apoptosis of cancer cells, not of normal cell in 1997, TRAIL has been considered as a new anticancer drug, which is specific for cancer cell line and also for cancer cell exhibiting resistance to other cancer drugs. However, several cancers, including breast, prostate, uterus, lung, liver and brain tumors, show TRAIL resistance, and it is also reported that continuous treatment of TRAIL to cancer cell line leads to the acquisition of resistance of cancer cell against TRAIL, even for those cells, which were sensitive to TRAIL.
TRAIL resistance mechanism is possibly caused due to the inhibitions of intracellular apoptosis signal transduction and DR 4/5s due to over-expression of decoy receptor, DcR 1 and 2, and in particular, the resistance acquisition due to change of intracellular signaling system is considered to be a more plausible explanation. The major cause in change of signal transduction is known to be over-expression of antiapoptotic protein, which inhibits proapoptotic proteins functions. Therefore, the development of TRAIL sensitizer, which increases cancer cell line specific apoptosis by overcoming TRAIL resistance, is an essentially-required research field.
It has been reported that the TRAIL-mediated cell death pathways play an important role in the diseases including rheumatoid arthritis, diabetic renal disease, and degenerative brain disease, as well as cancer (Journal of Korean Colledge of Rheumatology Vol. 12, No. 2, June, 2005; J AM Sco Nephrol 19: 904-914 (2008); Cell Death Differ. 2003 January; 10(1):134-41). A variety of approaches have thus been made to use TRAIL for relief and treatment of symptoms of autoimmune disease including arthritis, by inducing death of over-expressed immunocyte. Accordingly, TRAIL can be efficaciously used not only for treatment of the various cancers mentioned above, but also for treatment of T-cell-mediated autoimmune disease including experimental autoimmune encephalomyelitis (EAE), rheumatoid arthritis, and type I diabetes.
TIP41 gene, also called TIPRL (TOR Signaling Pathway Regulator-Like), was first isolated from yeast. TIP41 protein is known to be a negative regulator of TOR signaling system that reacts to rapamycin by interacting with TAP42 protein (Jacinto E et al, Mol. cell. 8 (5): 1017-26, 2001). Human TIP41 gene has 37% homogenous to yeasts TIP41, and is known to activate the signaling systems of MAPK and NF-kappaB (Matsuda A et al, Oncogene., 22 (21): 3307-3318, 2003). Unlike Tip41 in yeast, human TIP41 is expected to activate proliferation of cell, but the function of human TIP41 gene regarding liver cancer, stomach cancer or occurrence of cancer has never been reported yet.
Hence, the present inventors have completed the development by demonstrating that the apoptosis in TRAIL resistant cancer cell was significantly increased by the treatment of TRAIL and TIP41 depletion using siRNA (small interfering RNA) against TIP41. In addition, the induction of apoptosis was observed not only in liver cancer cell, but also in lung cancer cell and colorectal cancer cell, exhibiting TRAIL resistance. Furthermore, the effect was also confirmed in the size reduction of tumor on mice, which were injected with siRNA against TIP41 and TRAIL.